In recent years, in Korea, the intake of fats from foods has increased due to economic growth and the westernization of eating habits, and metabolic diseases such as hyperlipidemia, diabetes, hypertension, arteriosclerosis and fatty liver disease, which are caused by a lack of exercise, have increased.
Hyperlipidemia refers to a condition associated with elevated levels of lipids, such as free cholesterol, cholesterol esters, phospholipids and triglycerides, in blood. Hyperlipidemia can appear in three forms: (1) hypercholesterolemia, (2) hypertriglyceridemia, and (3) combined hyperlipidemia (hypercholesterolemia and hypertriglyceridemia). Hyperlipidemia is generally classified into primary hyperlipidemia and secondary hyperlipidemia. Primary hyperlipidemia is generally caused by genetic defects, whereas secondary hyperlipidemia is caused by various disease conditions, drugs and dietary habits. In addition, hyperlipidemia is also caused by a combination of the primary and secondary causes of hyperlipidemia. As criteria for the diagnosis of hyperlipidemia, a total cholesterol level of 220 mg/dl or higher and a triglyceride level of 150 mg/dl or higher are generally used.
There are various forms of cholesterol that naturally occur in mammals. Low-density (LDL) cholesterol is known to be harmful to health, and it is known that an increase in LDL cholesterol increases the risk of heart disease (Assman et al., Am. J. Card, 1996). In addition, high-density (HDL) cholesterol is regarded as good cholesterol and is essential for health, because it prevents atherosclerosis or the like.
Although hyperlipidemia does not show specific symptoms by itself, excessive lipids in blood adhere to the blood vessel walls to reduce the blood vessel size and cause atherosclerosis by inflammatory reactions. For this reason, coronary heart disease, cerebrovascular disease, obstruction of peripheral blood vessels, etc., can occur (E. Falk et al., Circulation, 1995). In addition, excessive blood lipids are accumulated in liver tissue, and thus can cause fatty liver disease. The fatty liver refers to a condition in which the ratio of fats in the weight of the liver is more than 5%. The fatty liver can be caused not only by excessive intake of fats, but also by intake of alcohol.
Current methods that are used to reduce blood lipid levels include dietary therapy, exercise therapy and drug therapy. However, dietary therapy or excise therapy is difficult to strictly control and perform, and the therapeutic effect thereof is also limited.
Drugs for reducing lipid levels, developed to date, include bile acid binding resin, cholesterol-lowering drugs such as HMG-CoA reductase inhibitors important in cholesterol biosynthesis, triglyceride-lowering drugs such as fibric acid derivatives and nicotinic acid, etc. However, these drugs were reported to have side effects such as hepatic toxicity, gastrointestinal disorder and carcinogenesis. Thus, there is an urgent need for the development of drugs that can be used to treat hyperlipidemia and related diseases (e.g., atherosclerosis and fatty liver disease) while having less side effects.
As a candidate for such drugs, oxyntomodulin has recently received attention. Oxyntomodulin is produced from pre-glucagon and is a peptide that can bind to both glucagon-like peptide-1 (GLP-1) and glucagon receptor to perform dual function. Because of such characteristics, oxyntomodulin has been studied for various purposes, including the treatment of obesity, hyperlipidemia and fatty liver disease. However, oxyntomodulin has a problem in that it should be administered at a high dose, because it has a short half-life in vivo and the activity thereof is insufficient for use in the treatment of obesity, hyperlipidemia and fatty liver disease.
Accordingly, the present inventors have developed an oxyntomodulin derivative having increased activity compared to native oxyntomodulin and have found that the oxyntomodulin derivative reduced the content and ratio of lipids in blood in a hyperlipidemia-induced hamster model, indicating that the derivative can be effectively used for the treatment of hyperlipidemia diseases, thereby completing the present invention.